Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

Abstract

G protein coupled receptor (GPCR) signalling is mediated by transactivation independent and transactivation dependent pathways. GPCRs transactivate protein tyrosine kinase receptors (PTKRs) and protein serine/threonine kinase receptors (PS/TKR). Since the initial observations of transactivation dependent signalling, there has been an effort to understand the mechanisms behind this phenomena. GPCR signalling has evolved to include biased signalling. Biased signalling, whereby selected ligands can activate the same GPCR that can generate multiple signals, but drive only a unique response. To date, there has been no focus on the ability of biased agonists to activate the PTKR and PS/TKR transactivation pathways differentially. As such, this represents a novel direction for future research. This review will discuss the main mechanisms of GPCR mediated receptor transactivation and the pathways involved in intracellular responses.

Adropin Stimulates Proliferation and Inhibits Adrenocortical Steroidogenesis in the Human Adrenal Carcinoma (HAC15) Cell Line

“…Based on experiments using the TGFβl kinase inhibitor, we confirmed that attenuation of steroidogenesis caused by adropin is mediated by the TGF-β signaling pathway, confirming the adropin-dependent transactivation mechanism. Other GPCR agonists such as thrombin ( 54 ), factor X ( 55 ), LPA ( 56 ) and endothelin-1 ( 57 ) lead to time-dependent activation of the TGF-β dependent signaling pathway. Previous research has shown that in vascular smooth muscle cells thrombin transactivation of the TGFBR1 based on cytoskeletal reorganization that activates Ras homolog member A (RhoA)/Rho-associated, coiled-coil containing protein kinase (ROCK) signaling, triggering the activation of integrin-dependent signaling and finally activating the large latent complex which holds TGF-β near the cell surface with the potential for activation of TGFBR1 ( 54 , 58 ).…”

“…Other GPCR agonists such as thrombin ( 54 ), factor X ( 55 ), LPA ( 56 ) and endothelin-1 ( 57 ) lead to time-dependent activation of the TGF-β dependent signaling pathway. Previous research has shown that in vascular smooth muscle cells thrombin transactivation of the TGFBR1 based on cytoskeletal reorganization that activates Ras homolog member A (RhoA)/Rho-associated, coiled-coil containing protein kinase (ROCK) signaling, triggering the activation of integrin-dependent signaling and finally activating the large latent complex which holds TGF-β near the cell surface with the potential for activation of TGFBR1 ( 54 , 58 ). Although our microarray study showed that adropin did not affect the expression of the RhoA/ROCK genes in the HAC15 cells, their expression was relatively high (data not shown), indicating that this intracellular mechanism of TGFBR1 transactivation may also occur in the HAC15 cell line.…”

Genes encoding neuropeptide receptors are epigenetic markers in patients with head and neck cancer: a site-specific analysis

“…Both GPCRs and receptor-tyrosine kinases (RTKs) regulate extensive signaling networks, control multiple cell functions, and participate in many diseases including cancer [ 31 ]. Transactivation of epidermal growth factors, which are RTKs, by GPCRs has been reported; hence, specific disruption of the crosstalk between these receptor types, even without inhibition of their activities, should substantially impede disease progression [ 32 ].…”

Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes

“…The cell signalling mechanisms involved in GAG synthesis and elongation are distinct [6,24]. The canonical TGF-β signalling pathway comprises direct carboxy-terminal phosphorylation of Smad2 by TGFBR1.…”

“…TGF-β signals via canonical carboxy terminal phosphorylation of R-Smads (Smad2 in vascular smooth muscle cells (VSMC)) and non-canonical linker region phosphorylation of R-Smads [3,4]. The role of TGF-β signalling in cell biology was greatly expanded when we showed that the paradigm of G Protein Coupled Receptor (GPCR) transactivation of protein tyrosine kinase receptors extended to the transactivation of serine/threonine kinase receptors and specifically the Type I TGF-β Receptor (TGFBR1) [5][6][7][8].…”